1. Field of the Invention
The presently disclosed and claimed invention relates generally to dental care and, more particularly, to the prevention of dental disease and demineralization of tooth enamel in orthodontic patients who wear orthodontic braces.
2. Description of the Background Art
Orthodontic treatment requires the use of compositions to bond appliances such as brackets, arch wires, retainers, braces, molar band, buccal tubes, elastomerics, adhesive systems or cements, and other paraphernalia to dental surfaces in the mouth, and/or seal the dental surfaces. Orthodontic brackets are appliances that are mechanically or adhesively affixed to teeth when a person receives orthodontic braces. The orthodontic brackets support another appliance, an orthodontic arch wire, which spans across the teeth and applies a corrective force to the teeth. Each orthodontic bracket has a smooth surface designed to abut against the surface of a tooth and an opposite surface designed to engage the arch wire. The brackets help facilitate and guide the movement/alignment of the teeth. Such brackets can be made of a metallic alloy, a composite material (i.e., medical-grade polyurethane), a ceramic material, or a combination of a composite material, a ceramic material and/or a metal alloy.
The orthodontic brackets and arch wire act together to facilitate and guide the movement/alignment of the teeth in order to alter the orientation of the teeth into a more bio-mechanically correct and aesthetically pleasing orientation.
Another appliance is the closing chain, which is used to assist with tooth movement and to close spaces between teeth. The closing chain may be an elastomeric chain made of a polyurethane material. Links of the chain are placed around the wings of the bracket. The chain lies “behind” or in front of the arch wire.
Elastomeric ligature ties (commonly referred to as “o-rings” or “ties”) may be placed around the “wings” of a bracket to hold an archwire in the slot of the bracket. These ties may be manufactured from a polyurethane material.
When present in the mouth, these compositions and/or appliances interfere with normal oral hygiene. As a result, the prevention and treatment of oral diseases, such as gingivitis, periondontitis, dental caries, and tooth enamel demineralization becomes very difficult during a course of orthodontic treatment. The compositions and/or appliances provide locations where food can accumulate and thereby constitute a source for the growth of bacteria and plaque. Accordingly, it would be desirable to make and apply these types of compositions and/or appliances in a manner which prevents the adverse effects of bacterial colonization and action.
Various efforts to provide antimicrobial action for medical type products to be implanted into the body have been considered in the past. For example, U.S. Pat. No. 5,906,466 describes an antimicrobial composition comprising antimicrobial silver compounds deposited on a physiologically inert oxide support material. In Japanese Patent Abstract No. 08041611, an alloy exhibiting antimicrobial properties is disclosed.
Attempts have been made to solve various aspects of this problem in the field of orthodontic appliances. For example, in U.S. Pat. No. 5,068,107 (issued to Hollibush et al. on Nov. 26, 1991 and expressly incorporated herein by reference), an elastic retainer member, such as formed by an elastic polymeric material, is provided with a dentally active pharmacological agent, such as halide salt and various compositions that contain fluoride. The agent is released in the mouth. Such a product suffers from the defect of the agent being depleted over time, thereby requiring replacement of the appliance. Also, this approach is not easily used for metal orthodontic appliances. U.S. Pat. No. 5,716,208 (issued to Forman et al. on Feb. 10, 1998 and expressly incorporated herein by reference), discloses an orthodontic bracket to be attached to a tooth that has an outer coating that contains an organic antimicrobial agent, the preferred one disclosed being 2,4,4′-trichloro-2′-hydroxy-diphenyl ether (triclosan) which is a halogenated diphenyl ether. Triclosan is an organic compound, and therefore suffers from the disadvantage that antibiotic resistance can develop over time with continued use. Furthermore, triclosan is suspected of inducing skin irritation.
Selenium (Se) is among the most toxic of all known minerals. Its toxicity symptoms in horses were most likely described by Marco Polo while traveling the silk road in China. In the 1920's, loss of livestock in parts of the western and central United States was severe. Those losses of livestock were investigated by the United States Department of Agriculture Experiment Station in South Dakota. In 1934, the cause of the loss of livestock was traced by the Experiment Station to the element selenium which was high in certain soils and high secondarily in plants from several species of Astragalus (vetch), Xylorrhiza (woody aster), Conopsis (goldenrod) and Stanleya (Prince's Plume). Ingestion of these and other Se containing plants by livestock often proved to be fatal.
Throughout the period of time between the discovery of selenium toxicity in livestock in 1934 and 1988, many hypotheses were put forth to explain the mechanism by which many but not all compounds of selenium were toxic. None of these theories of selenium toxicity proved satisfactory in fully explaining why selenium was toxic. In 1989, Seko et al. (In: Proceedings of the fourth international symposium on selenium and medicine (ed., Wendel, A.) pp. 70-73, Springer-Verlag, Heidelberg, Germany, (1989)), reported that selenite, (SeO3), an inorganic form of Se, reacted with a thiol, glutathione, (GSH), to produce superoxide (O2−). Since superoxide is a known toxicant, this raised the possibility that all selenium compounds that are toxic might generate superoxide. Through the testing of many selenium compounds, it was found that the inorganic compounds, SeO3 and selenium dioxide (SeO2) were able to generate O2− and hydrogen peroxide (H2O2) when presented with a thiol, such as glutathione, cysteine (CysSH), or dithiothreitol D(SH)2. Furthermore, it was found that all diselenides tested of the composition RSeSeR likewise would generate O2− and H2O2 when presented with any of the before mentioned thiols.
In 1947, Feigl et al. (Analytical Chemistry, 19:351-353 (1947)), reported that selenium could catalyze a redox reaction involving sulfide oxidation. This soon became a common test for selenium using methylene blue. This reaction was further studied by others using different selenium compounds and thiols, demonstrating catalysis for some but not all selenium compounds. See, West et al. (Analytic Chemistry, 40:966-968 (1968)); Levander et al. (Biochemistry, 12:4591-4595 (1973)), Rhead et al. (Biorganic Chemistry, 3:225-242 (1974)). The selenium catalytic activity of selenocystine (RSeSeR) in the presence of thiols was reported in 1958. It is now believed that all of the foregoing reactions of selenium compounds produce superoxide. See, Xu et al. (Advances in Free Radical Biology and Medicine, 1:35-48 (1991)); Xu et al. (Huzahong Longong Daxus Xuebao, 19:13-19 (1991)); Kitahara et al. (Archives of toxicology, 67:497-501 (1993)); Chaudiere et al. (Archives of Biochemistry and Biophysics, 296:328-336 (1992)).
A summation of the large body of experimental data on selenium toxicity, catalysis and carcinostatic activity is as follows:
(1) The selenium compounds, SeO2 and SeO3, react with thiols to produce a selenodithiol of the configuration (RSSeSR). This compound is not toxic per se nor is it carcinostatic. The toxic carcinostatic form of RSeR is the reduced selenide anion, RSe−. This selenopersulfide form of Se is catalytic as shown by the inhibition of both catalysis and superoxide generation by iodoacetic acid and mercaptosuccinic acid.
(2) Selenium compounds of the configuration (RSeSeR) or (RSeSeR′) react with thiols to produce the reduced selenite anion RSe− or R′Se−. This selenopersulfide form of Se is catalytic as shown by the inhibition of both catalysis and superoxide generation by iodoacetic acid and mercaptosuccinic acid.
(3) Organic selenium catalysts of the configuration RSe−, the selenopersulfide anion, is catalytic in the presence of thiols, and RSe− continues to generate superoxide (O2−) ion as long as sufficient concentrations of O2− and thiol are in the medium. Selenium compounds derived from selenite or selenium dioxide reacting with glutathione (GSH) are converted to elemental selenium (Se−) as follows; SeO3 (SeO2)+2GSH-2GSSeSG-2GSSG+Se−. Elemental selenium (Se−) is non-catalytic and not toxic.
(4) Compounds of selenium of the configuration RSe− are toxic due to the catalytic acceleration of thiol oxidation which produces O2−, H2O2 and the more toxic free radical, the hydroxyl radical (OH). This chemistry had been discussed by Misra (J. Biol. Chem., 249:2151-2155 (1974)) for the spontaneous oxidation of thiols. The association of rapid thiol catalysis by selenium compounds of the configuration RSe− and the toxicity from which it produced free radicals and reactive toxic oxygen products was recognized in 1992 by one of the inventors.
At least since the 1870s, silver has been recognized as an antibacterial agent, and has been particularly noted for its ability to resist the development of drug-resistance in target bacteria. In general, silver cations (Ag+) are thought to possess antimicrobial activity because they are highly reactive chemical structures that bind strongly to electron donor groups containing sulfur, oxygen, or nitrogen that are present in microbial targets. The biological target molecules generally contain all these components in the form of thio, amino, imidazole, carboxylate, and phosphate groups. Silver ions act by displacing other essential metal ions such as calcium or zinc. The direct binding of silver ions to bacterial DNA may also serve to inhibit a number of important transport processes, such as phosphate and succinate uptake, and can interact with cellular oxidation processes as well as the respiratory chain. The silver ion-induced antibacterial killing rate is directly proportional to silver ion concentrations, typically acting at multiple targets. Indeed, for silver ion-based antimicrobial articles and devices to be effective as antimicrobial vectors, the silver ions with which they are impregnated must be slowly released into the environment so that they are free to contact and inhibit the growth of destructive microbes in the environment. Accordingly, the antimicrobial activity of silver-coated and silver-impregnated articles and devices is dependent upon the controlled release rate of the unbound, free silver ions they carry, and the continued antimicrobial efficacy of such silver-based antimicrobials is necessarily limited by the supply of free silver ions they retain.
The inventor's previous work, as disclosed and claimed in U.S. Pat. No. 5,783,454 (issued Jul. 21, 1998); U.S. Pat. No. 5,994,151 (issued Nov. 30, 1999); U.S. Pat. No. 6,033,917 (issued Mar. 7, 2000); U.S. Pat. No. 6,040,197 (issued Mar. 21, 2000); U.S. Pat. No. 6,043,098 (issued Mar. 28, 2000); U.S. Pat. No. 6,043,099 (issued Mar. 28, 2000); and U.S. Pat. No. 6,077,714 (issued Jun. 20, 2000); all issued to Spallholz et al. and expressly incorporated herein by reference, discloses methods for making selenium-carrier conjugates by covalently attaching (i) an organic selenium compound selected from the group consisting of RSeH, RSeR, RSeR′, RSeSeR and RSeSeR′, wherein R and R′ are each an aliphatic residue containing at least one reactive group selected from the group consisting of aldehyde, amino, alcoholic, phosphate, sulfate, halogen or phenolic reactive groups and combinations thereof, to (ii) a carrier having a constituent capable of forming a covalent bond with said reactive groups of said selenium compound to produce a selenium-carrier conjugate which is capable of specific attachment to a target site. The carrier may be a protein, such as an antibody specific to a bacteria, virus, protozoa, or cell antigen, including without limitation, cell surface antigens, a peptide, carbohydrate, lipid, vitamin, drug, lectin, plasmid, liposome, nucleic acid or a non-metallic implantable device, such as an intraocular implant or a vascular shunt.
The '454 patent demonstrates the cytotoxicity of selenofolate of the configuration Folate-SeSeR, which produces superoxide in the presence of glutathione, as measured by lucigenin chemiluminescence; this modified vitamin compound is cytotoxic to cells upon uptake in a dose dependent manner. The '454 patent also demonstrates the ability of selenocystamine attached to plastic or a cellulose matrix to inhibit cellular growth.
However, the selenium-carrier conjugates of the prior art (as taught in the various patents listed above) require covalent attachment of the selenium compound to the carrier molecule in order to be effective, and the R and R′ groups attached to the selenium must be aliphatic groups. In addition, the leaving groups generated when RSe− is produced, as taught by the prior art, are toxic. Therefore, there is a need for sustainable and effective biocidal agents that both avoid the formation of resistant microbes and can be adapted for use in dental and/or orthodontic applications which overcome the disadvantages and defects of the prior art. It is to such improved biocidal compositions, and methods of production and use thereof, that the presently disclosed and claimed invention is directed.